WO2011073705A1 - Novel process for the preparation of piperazine compounds and hydrochloride salts thereof - Google Patents
Novel process for the preparation of piperazine compounds and hydrochloride salts thereof Download PDFInfo
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- WO2011073705A1 WO2011073705A1 PCT/HU2010/000144 HU2010000144W WO2011073705A1 WO 2011073705 A1 WO2011073705 A1 WO 2011073705A1 HU 2010000144 W HU2010000144 W HU 2010000144W WO 2011073705 A1 WO2011073705 A1 WO 2011073705A1
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- Prior art keywords
- general formula
- optionally substituted
- compound
- alkyl
- temperature
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000003840 hydrochlorides Chemical class 0.000 title claims abstract description 7
- 150000004885 piperazines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 11
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 10
- 239000012453 solvate Chemical group 0.000 claims abstract description 10
- 150000001412 amines Chemical class 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims abstract description 7
- 150000004677 hydrates Chemical group 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 238000011065 in-situ storage Methods 0.000 claims abstract description 5
- 239000012442 inert solvent Substances 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 10
- -1 chloroformate ester Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- PAFZNILMFXTMIY-UHFFFAOYSA-N Cyclohexylamine Natural products NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000000725 suspension Substances 0.000 description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000012153 distilled water Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- PLOZPRNHVXJFFC-WKILWMFISA-N C1C[C@@H](NC(=O)OC)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 Chemical compound C1C[C@@H](NC(=O)OC)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 PLOZPRNHVXJFFC-WKILWMFISA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- GIAOVZPOOUDJDR-UHFFFAOYSA-N 4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]-1-(dimethylamino)cyclohexane-1-carboxamide Chemical compound C1CC(N(C)C)(C(N)=O)CCC1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 GIAOVZPOOUDJDR-UHFFFAOYSA-N 0.000 description 1
- RDPGZIWCXXEEFN-UHFFFAOYSA-N 4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]-1-(dimethylamino)cyclohexane-1-carboxamide;hydrochloride Chemical compound Cl.C1CC(N(C)C)(C(N)=O)CCC1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 RDPGZIWCXXEEFN-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- OSFYUOBMIMRRQJ-SHTZXODSSA-N C1C[C@@H](N)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 Chemical compound C1C[C@@H](N)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 OSFYUOBMIMRRQJ-SHTZXODSSA-N 0.000 description 1
- WZSUCHUYLQMKGD-IYARVYRRSA-N C1C[C@@H](NC(=O)OC(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 Chemical compound C1C[C@@H](NC(=O)OC(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 WZSUCHUYLQMKGD-IYARVYRRSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- NBYQXBYMEUOBON-UHFFFAOYSA-N carbamothioyl chloride Chemical compound NC(Cl)=S NBYQXBYMEUOBON-UHFFFAOYSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- WQJONRMBVKFKOB-UHFFFAOYSA-N cyanatosulfanyl cyanate Chemical compound N#COSOC#N WQJONRMBVKFKOB-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Definitions
- the invention relates to a new process for the preparation of trans N- ⁇ 4- ⁇ 2-[4-(2,3- dichlorophenyl)-piperazine-l-yl] -ethyl ⁇ -cyclohexyl ⁇ -carbamide compounds of general formula (I)
- R-O-CO-Z (VI) wherein R is C 1- straight or branched alkyl, partially or fully halogenated C 1-2 alkyl or phenyl, Z is -O-R or -X, wherein R is as described above, X is halogen,
- Ri and R 2 represent independently
- optionally substituted monocyclic, bicyclic or tricyclic C 3-14 cycloalkyl group, or - R ⁇ and R 2 together with the adjacent nitrogen may form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms, selected from oxygen, nitrogen or sulphur atoms
- the invention relates to a new process for the preparation of compounds of general formula (I)
- R] and R 2 represent independently
- optionally substituted monocyclic, bicyclic or tricyclic C 3-14 cycloalkyl group, or - Ri and R 2 together with the adjacent nitrogen may form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen or sulphur atoms
- hydrochloride salts and/or hydrates and/or solvates thereof.
- the aryl group represents for example phenyl, tolyl, naphthyl or phenanthryl groups.
- R-O-CO-Z (VI) wherein R is C 1-6 alkyl with straight or branched chain, partially or fully halogenated C 1-2 alkyl or phenyl, Z is -O-R or -X, wherein R is as described above, X is halogen to give a compound of general formula (IV) wherein R is C 1-6 alkyl or fully halogenated C 1-2 alkyl group. Then the compound of general formula (IV) obtained is reacted with an amine of general formula (V)
- Suitable solvents which can be used in the process according to the invention include inert, water immiscible solvents, for example toluene, dichloromethane, chlorobenzene or xylene.
- the solvent is dichloromethane.
- Suitable bases which can be used in the process according to the invention include organic bases, preferably tertiary amines, for example triethylamine.
- the alkyl group when R represents partially halogenated alkyl group, the alkyl group may be for example chloromethyl or chloroethyl group and when R represents fully halogenated alkyl group, the alkyl group may be for example trichloromethyl or pentachloroethyl group.
- the carbonic acid derivative is chloroformic acid ester or bis- trichloromethylcarbonate.
- the reaction between the compounds of general formula (IV) and (V) may be carried out in such a manner, that after an isolation step the urethane compound of general formula (IV) is reacted with an amine of general formula (V).
- the above reaction is preferably may be performed in situ in an inert solvent in such a way that an appropriate amine of general formula (V) is added to the reaction mixture of formulas of (III) and (VI). In this latter case, starting from the compound of formula (III) via the non-isolated compound of general formula (IV) we get the compound of general formula (I) in high yield of over 90%.
- the advantages of the process according to the invention are as follows: the yield increases from 52-65% to 95%, and by using the procedure besides the N-monosubstituted compounds of formula (I) N-disubstituted compounds can be obtained too.
- the invention relates to a process for the preparation the trans N- ⁇ 4- ⁇ 2-[4-(2,3- dichlorophenyl)-piperazine-l-yl] -ethyl ⁇ -cyclohexyl ⁇ -carbamide base of general formula (I) and the hydrochloride salts thereof.
- the base is not isolated but after an aqueous dilution the reaction mixture is acidified with hydrochloric acid to pH 2-4, then the reaction mixture is converted to an aqueous suspension by distillation and the hydrochloride salt of the compound of general formula (I) is isolated in high purity ad yield of over 90%.
- reaction mixture obtained was stirred at a temperature between 20-25°C for 3 hours then extracted with 3x150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue was recrystallized from methanol. In this manner 4.5 g of the title product was obtained.
- the reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 130 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
- IP A isopropyl alcohol
- the solution obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (100 ml, 0.3 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 100 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 120 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
- IP A isopropyl alcohol
- the reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes 100 ml of distilled water was added to the reaction mixture under stirring. Then the pH of the aqueous phase is adjusted to 2-3 by adding concentrated hydrochloric acid and the reaction mixture was concentrated to 130 ml, additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
- IP A isopropyl alcohol
- the reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0,12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added and the pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 130 ml under vacuum then additional 70 ml of water was added and the mixture was concentrated to 170 ml. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
- IP A isopropyl alcohol
- the reaction mixture obtained was added to a solution of methylamine in isopropyl alcohol (IP A) (60 ml, 12.5 g/100 ml) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 130 ml of distilled water was added then the pH of the aqueous phase was adjusted to
- reaction mixture was added to the solution of 10.44 g (0.12 mol) morpholine in 70 ml of isopropyl alcohol (IP A) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C.
- IP A isopropyl alcohol
- 100 ml of distilled water was added under stirring and the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid.
- the reaction mixture was concentrated to 130 ml under vacuum and additional 100 ml of distilled water was added. Volume of the reaction mixture was decreased to 150 ml in vacuum.
- the suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
- the reaction mixture obtained was added to a solution of 10.44 g of (0.12 mol) morpholine in 70 ml of isopropyl alcohol (IP A) cooled to a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at 0-10°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring then the pH of the aqueous phase was adjusted to 2-3. The reaction mixture was concentrated to 130 ml under vacuum and further 100 ml of distilled water was added. Then the volume of the reaction mixture was decreased to 150 ml under vacuum. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
- IP A isopropyl alcohol
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to a new process for the preparation of compounds of general formula (I) wherein R1 and R2 represent independently hydrogen or C1-6 alkyl with straight or branched chain optionally substituted with aryl group; or C2-7 alkenyl containing 1-3 double bonds; or monocyclic, bicyclic or tricyclic aryl optionally substituted with one or more C1-6 alkoxy, trifiuoro-C1-6 alkoxy, C1-6-alkoxycarbonil, C1-6alkanoyl, aryl, C1-6 alkylthio, halogen or cyano; or optionally substituted monocyclic, bicyclic or tricyclic C3-14 cycloalkyl group; R1 and R2 together with the adjacent nitrogen form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen, or sulphur atoms and hydrochloric acid salts and/or hydrates and/or solvates thereof, by dissolving or suspending trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexylamine of formula (III) or a salt or a hydrate or a solvate thereof in an inert solvent in the presence of a base then adding a carbonic acid derivative of general formula (VI) wherein R is alkyl with C1-6 straight or branched chain, partially or fully halogenated C1-2 alkyl or phenyl, Z is -O-R or -X, wherein R is as described above, X is halogen, and reacting the compound of general formula (IV) obtained wherein R is as described above, in situ or, optionally in isolated state with an amine of general formula (V) wherein R1 and R2 are as described above to obtain the compound of general formula (I) and then optionally forming the hydrochloride salts and/or hydrates and/or solvates thereof.
Description
NOVEL PROCESS FOR THE PREPARATION OF PIPERAZINE COMPOUNDS AND HYDROCHLORIDE SALTS THEREOF
FIELD OF THE INVENTION
The invention relates to a new process for the preparation of trans N- {4- {2-[4-(2,3- dichlorophenyl)-piperazine-l-yl] -ethyl }-cyclohexyl} -carbamide compounds of general formula (I)
- hydrogen or
- C1-6 alkyl with straight or branched chain optionally substituted with aryl group, or
- Ri and R2 together with the adjacent nitrogen atom may form an optionally substituted, saturated or unsaturated, monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen or sulphur atoms
- C2-7 alkenyl containing 1-3 double bonds, or
- monocyclic, bicyclic or tricyclic aril group optionally substituted with one or more C1-6- alkoxy, trifluoro-C1-6-alkoxy, C1-6 alkoxycarbonyl, C1-6 alkanoyl, aryl, C1-6 alkylthio, cyano groups or halogen atom
- optionally substituted monocyclic, bicyclic, or tricyclic C3-j4 cycloalkyl group and hydrochloride salts and/or hydrates and/or solvates thereof.
BACKGROUND OF THE INVENTION
The base form of the compounds of general formula (I) was originally disclosed in the Hungarian Patent Specification No. P0302451. In the specification three reaction routes (A, B, C methods) are given for the preparation of the base form of compounds of formula (I). In the method„A" a suitable amine is reacted with a (thio)carbamoylchloride to give the end products of general formula (I). According to the A Method of P0302451 the "A" procedure gives the product with a yield of only 65% and with very long reaction time. According to Method B an iso(thio)cyanate is reacted with an amine compound. Drawback of the "B" process is that using this procedure only the compound of general formula (I) may be prepared wherein one of the R\ and R2 groups represents hydrogen. According to the "C" Method of P0302451 a suitable amine is transformed to an iso(thio)cyanate derivative then this iso(thio)cyanate derivative is reacted with an amine to give the desired end products of formula (I). The total yield of Method C is very low, only 52%.
Drawbacks of the "A" and "C" procedures are the long reaction times (48 and 20 hours) and poor yields (65% and 52%). Besides, in the "A" and "C" procedures the end product obtained should be purified in an additional purification (recrystallization) step to give the product in suitable quality. SUMMARY OF THE INVENTION
Our aim was to develop a process which provides both unsubstituted and mono- and disubstituted carbamide compounds of general formula (I) with excellent yield.
We have surprisingly found that by reacting trans 4-{2-[4-(2,3-dichlorophenyl)- piperazine-l-yl]-ethyl}-cyclohexylamine of formula (III)
or a salt and/or a hydrate and/or a solvate thereof with a carbonic acid derivative of general formula (VI)
R-O-CO-Z (VI) wherein R is C1- straight or branched alkyl, partially or fully halogenated C1-2 alkyl or phenyl, Z is -O-R or -X, wherein R is as described above, X is halogen,
then reacting the compound of general formula (IV) obtained
with an amine derivative of general formula (V)
NH
R2
(V) wherein
Ri and R2 represent independently
- hydrogen or
C1-6 alkyl with straight or branched chain optionally substituted with aryl group, or C2-7 alkenyl containing 1 -3 double bonds, or
- monocyclic, bicyclic or tricyclic aryl optionally substituted with one or more C1-6 alkoxy, trifluoro-Ci-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alcanoyl, aryl, C1-6 alkyltio, halogen, or cyano groups, or
- optionally substituted monocyclic, bicyclic or tricyclic C3-14 cycloalkyl group, or
- R\ and R2 together with the adjacent nitrogen may form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms, selected from oxygen, nitrogen or sulphur atoms
get the compounds of general formula (I)
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a new process for the preparation of compounds of general formula (I)
- hydrogen or
- Ci-6 alkyl with straight or branched chain optionally substituted with aryl group, or C2-7 alkenyl containing 1-3 double bonds, or
- monocyclic, bicyclic or tricyclic aryl group optionally substituted with one or more C1-6 alkoxy, trifluoro-C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alcanoyl, aryl, Ci-6 alkyltio, halogen, or cyano groups, or
optionally substituted monocyclic, bicyclic or tricyclic C3-14 cycloalkyl group, or - Ri and R2 together with the adjacent nitrogen may form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen or sulphur atoms
and hydrochloride salts, and/or hydrates and/or solvates thereof.
In the meanings of R\ and R2 the aryl group represents for example phenyl, tolyl, naphthyl or phenanthryl groups.
Performing the process according to the invention the trans 4-{2-[4-(2,3- dichlorophenyl)-piperazine-l-yl] -ethyl }-cyclohexyl-amine compound of formula (III)
R-O-CO-Z (VI) wherein R is C1-6 alkyl with straight or branched chain, partially or fully halogenated C1-2 alkyl or phenyl, Z is -O-R or -X, wherein R is as described above, X is halogen to give a compound of general formula (IV)
wherein R is C1-6 alkyl or fully halogenated C1-2 alkyl group. Then the compound of general formula (IV) obtained is reacted with an amine of general formula (V)
R
\
NH
/
wherein Ri and R2 are as described above to give a compound of general formula (I). The above reaction may be carried out in situ in an inert solvent or after the isolation of the compound of general formula (IV).
Suitable solvents, which can be used in the process according to the invention include inert, water immiscible solvents, for example toluene, dichloromethane, chlorobenzene or xylene. In a preferred embodiment of the invention the solvent is dichloromethane.
Suitable bases, which can be used in the process according to the invention include organic bases, preferably tertiary amines, for example triethylamine.
In the substituents meanings of the carbonic acid derivatives of general formula (VI) when R represents partially halogenated alkyl group, the alkyl group may be for example chloromethyl or chloroethyl group and when R represents fully halogenated alkyl group, the alkyl group may be for example trichloromethyl or pentachloroethyl group. In a preferred embodiment of the invention the carbonic acid derivative is chloroformic acid ester or bis- trichloromethylcarbonate.
Performing the process according to the invention the reaction between the compounds of general formula (IV) and (V) may be carried out in such a manner, that after an isolation step the urethane compound of general formula (IV) is reacted with an amine of
general formula (V). However, owing to the bad isolability of compounds of general formula (IV) the above reaction is preferably may be performed in situ in an inert solvent in such a way that an appropriate amine of general formula (V) is added to the reaction mixture of formulas of (III) and (VI). In this latter case, starting from the compound of formula (III) via the non-isolated compound of general formula (IV) we get the compound of general formula (I) in high yield of over 90%.
In the light of the technical literature the advantages of the process according to the invention are as follows: the yield increases from 52-65% to 95%, and by using the procedure besides the N-monosubstituted compounds of formula (I) N-disubstituted compounds can be obtained too.
The invention relates to a process for the preparation the trans N-{4-{2-[4-(2,3- dichlorophenyl)-piperazine-l-yl] -ethyl }-cyclohexyl} -carbamide base of general formula (I) and the hydrochloride salts thereof.
In an embodiment of the invention to give the trans N-{4-{2-[4-(2,3- dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl}-carbamide base of general formula (I) work-up of the reaction mixture is carried out in such a manner that after an aqueous dilution the reaction mixture is extracted with an organic solvent and the base compound of formula (I) may be isolated by a known manner preferably by removing the solvent.
In a preferred embodiment of the invention the base is not isolated but after an aqueous dilution the reaction mixture is acidified with hydrochloric acid to pH 2-4, then the reaction mixture is converted to an aqueous suspension by distillation and the hydrochloride salt of the compound of general formula (I) is isolated in high purity ad yield of over 90%.
EXAMPLES
The invention is illustrated by the following non-limiting examples.
Example 1
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid methylester 6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The so obtained suspension was added to a solution of 2.3 ml (0.03 mol) methyl chloroformate in 25 ml of dichloromethane at a temperature between 5-10°C. The reaction mixture obtained was stirred at a temperature between 20-25°C for 3 hours then extracted with 3x150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue was recrystallized from methanol. In this manner 4.5 g of the title product was obtained.
Yield: 72 %.
Melting point: 143-147 °C
Example 2
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid isopropylester
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C-on for one hour. The suspension was added to a solution of 3.7 g (0.03 mol) of isopropyl chloroformate in 30 ml of toluene at a temperature between 5-10°C. The reaction mixture was stirred at a temperature between 20-25°C for 3 hours and then extracted with 3x150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue obtained was recrystallized from isopropanole.
In this manner 4,4 g of title compound was obtained.
Yield: 67 %.
Melting point: 128-131°C
Example 3
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 130 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.6 g of title compound was obtained.
Yield: 95 %
Melting point: 208-211 °C
Example 4
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyI}-N,N-dimethylcarbamoyl- cyclohexylamine 4.4 g (0.011 mol) of trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}- cyclohexyl)-carbamic acid methylester was dissolved in 120 ml of dichloromethane. The solution obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (100 ml, 0.3 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 100 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 120 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 4.3 g of title compound was obtained.
Yield: 95 %
Melting point: 208-211 °C
Example 5
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine hydrochloride 6.45 g (0.015 mol) dihydrochloride of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes 100 ml of distilled water was
added to the reaction mixture under stirring. Then the pH of the aqueous phase is adjusted to 2-3 by adding concentrated hydrochloric acid and the reaction mixture was concentrated to 130 ml, additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained.
Yield: 96 %
Melting point: 221-224 °C
Example 6
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoil- cyclohexylamine hydrochloride 6.72 g (0.015 mol) dihydrochloride monohydrate of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25 °C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0,12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added and the pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 130 ml under vacuum then additional 70 ml of water was added and the mixture was concentrated to 170 ml. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained.
Yield: 96 %.
Melting point: 221-224 °C
Example 7
1- Trans {4-[2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl]-cyclohexyl}carbamide
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 160 ml of dichloromethane and 12.8 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 75 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of ammonia in methanol (110 ml, 17g/ 100ml) cooled at a temperature between 0-(- 10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes the reaction mixture was concentrated to 100 ml in vacuum then 800 ml of distilled water was added. The suspension was stirred at 20- 25°C for one hour and the product obtained was isolated by filtration.
In this manner 5.6 g of title compound was obtained.
Yield: 94 %.
Melting point: 221-224 °C
Example 8
Trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl}-N'- methylcarbamide hydrochloride
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of methylamine in isopropyl alcohol (IP A) (60 ml, 12.5 g/100 ml) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 130 ml of distilled water was added then the pH of the aqueous phase was adjusted to
2- 3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 120
ml in vacuum and additional 70 ml of distilled water was added. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.6 g of title compound was obtained.
Yield: 95 %.
Melting point: 230-255 °C.
Example 9
Trans N-{4-{2-[4-(2,3-dichIorophenyl)-piperazine-l-yl]-ethyl}-cyclohexylcarbamide hydrochloride
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 160 ml of dichloromethane and 12.8 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 75 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of ammonia in methanol (110 ml, 17 g/ 100 ml) cooled at a temperature between 0-(- 10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at 0-10°C for 30 minutes the reaction mixture was concentrated to 20 ml in vacuum then 140 ml of distilled water was added. The pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The suspension was stirred at a temperature between 20- 25°C for one hour and the product obtained was isolated by filtration. In this manner 5.86 g of title compound was obtained.
Yield: 90%.
Melting point: 250-253 °C (decomp.).
Example 10
Trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyI}-cycIohexyl}-morpholine-4- carbonic amide 6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10) °C for one hour. The so obtained reaction mixture was added to the solution of 10.44 g (0.12 mol) morpholine in 70 ml of isopropyl alcohol (IP A) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at 0-10°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring and the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 130 ml under vacuum and additional 100 ml of distilled water was added. Volume of the reaction mixture was decreased to 150 ml in vacuum. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.55 g of title compound was obtained.
Yield: 93 %.
Melting point: 204-206°C (decomp).
Example 11
Trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl}-morpholine-4- carbonic amide hydrochloride
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25 °C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane ata temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 10.44 g of (0.12 mol) morpholine in 70 ml of isopropyl alcohol (IP A) cooled to a
temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at 0-10°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring then the pH of the aqueous phase was adjusted to 2-3. The reaction mixture was concentrated to 130 ml under vacuum and further 100 ml of distilled water was added. Then the volume of the reaction mixture was decreased to 150 ml under vacuum. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 7.1 g of title product was obtained.
Yield: 94 %.
Melting point: 197 °C (decomp.).
Claims
1. Process for the preparation of compounds of general formula (I)
wherein R\ and R2 represent independently
- hydrogen or
- C1-6 alkyl with straight or branched chain optionally substituted with aryl group, or
- C2-7 alkenyl containing 1 -3 double bonds, or
- monocyclic, bicyclic or tricyclic aryl optionally substituted with one or more CI -6 alkoxy, trifluoro-C!.6 alkoxy, C1-6-alkoxycarbonil, C1-6alkanoyl, aryl, C1-6 alkylthio, halogen or cyano, or
optionally substituted monocyclic, bicyclic or tricyclic C3-14 cycloalkyl group, Ri and R2 together with the adjacent nitrogen form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen, or sulphur atoms
and hydrochloric acid salts and/or hydrates and/or solvates thereof characterized in that dissolving or suspending trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-il]-ethyl}- cyclohexylamine of formula (III)
R-O-CO-Z (VI) wherein R is alkyl with C 1-6 straight or branched chain, partially or fully halogenated C1-2 alkyl or phenyl, Z is -O-R or -X, wherein R is as described above, X is halogen, and reacting the compound of general formula (IV) obtained
wherein R is as described above,
in situ or, optionally in isolated state with an amine of general formula (V)
NH
/
R2
wherein R\ and R2 are as described above to obtain the compound of general formula (I) and then optionally
forming the hydrochloride salts and/or hydrates and/or solvates thereof.
2. A process according to claim 1 characterized in that the carbonic acid derivative of general formula (VI) is a chloroformate ester or bis(trichloromethyl)carbonate.
3. A process according to claim 1 characterized in that the reaction of compounds of general formula (IV) and (V) is carried out in situ without isolation of the compound of general formula (IV).
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|---|---|---|---|
| HUP0900790 | 2009-12-17 | ||
| HU0900790A HUP0900790A2 (en) | 2009-12-17 | 2009-12-17 | A new process for the preparation of piperazine and their hydrochloric salts |
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| Publication Number | Publication Date |
|---|---|
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014180165A1 (en) | 2013-05-08 | 2014-11-13 | 上海医药工业研究院 | Benzoisothiazole compounds and use in preparation of antipsychotic drugs |
| CN108586389A (en) * | 2018-06-29 | 2018-09-28 | 成都福柯斯医药技术有限公司 | A kind of new method of synthesis Cariliprazine |
| WO2018229794A1 (en) * | 2017-06-13 | 2018-12-20 | Cipla Limited | Amorphous form of cariprazine |
| CN110372557A (en) * | 2019-08-06 | 2019-10-25 | 上海勋和医药科技有限公司 | Hexamethylene amine D3/D2Acceptor portion agonist |
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|---|---|---|---|---|
| WO2005012266A1 (en) * | 2003-08-04 | 2005-02-10 | Richter Gedeon Vegyészeti Gyár Rt. | (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists |
| WO2008142461A1 (en) * | 2007-05-18 | 2008-11-27 | Richter Gedeon Nyrt. | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
| WO2010070371A1 (en) * | 2008-12-18 | 2010-06-24 | Richter Gedeon Nyrt. | Process for the preparation of piperazine derivatives |
| WO2010070370A1 (en) * | 2008-12-18 | 2010-06-24 | Richter Gedeon Nyrt. | Process for the preparation of piperazine compounds and hydrochloride salts thereof |
-
2009
- 2009-12-17 HU HU0900790A patent/HUP0900790A2/en unknown
-
2010
- 2010-12-13 TW TW099143483A patent/TW201144289A/en unknown
- 2010-12-17 WO PCT/HU2010/000144 patent/WO2011073705A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005012266A1 (en) * | 2003-08-04 | 2005-02-10 | Richter Gedeon Vegyészeti Gyár Rt. | (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists |
| HUP0302451A2 (en) | 2003-08-04 | 2005-05-30 | Richter Gedeon Vegyészeti Gyár Rt. | (thio)carbamoyl-cyclohexane derivatives, process for producing them and pharmaceutical compositions containing them |
| WO2008142461A1 (en) * | 2007-05-18 | 2008-11-27 | Richter Gedeon Nyrt. | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
| WO2010070371A1 (en) * | 2008-12-18 | 2010-06-24 | Richter Gedeon Nyrt. | Process for the preparation of piperazine derivatives |
| WO2010070370A1 (en) * | 2008-12-18 | 2010-06-24 | Richter Gedeon Nyrt. | Process for the preparation of piperazine compounds and hydrochloride salts thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014180165A1 (en) | 2013-05-08 | 2014-11-13 | 上海医药工业研究院 | Benzoisothiazole compounds and use in preparation of antipsychotic drugs |
| WO2018229794A1 (en) * | 2017-06-13 | 2018-12-20 | Cipla Limited | Amorphous form of cariprazine |
| CN108586389A (en) * | 2018-06-29 | 2018-09-28 | 成都福柯斯医药技术有限公司 | A kind of new method of synthesis Cariliprazine |
| CN110372557A (en) * | 2019-08-06 | 2019-10-25 | 上海勋和医药科技有限公司 | Hexamethylene amine D3/D2Acceptor portion agonist |
| WO2021022890A1 (en) * | 2019-08-06 | 2021-02-11 | 上海勋和医药科技有限公司 | Cyclohexanamine d3/d2 receptor partial agonist |
| CN110372557B (en) * | 2019-08-06 | 2021-05-18 | 上海勋和医药科技有限公司 | Cyclohexanamines D3/D2Partial receptor agonists |
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| HU0900790D0 (en) | 2010-03-01 |
| HUP0900790A2 (en) | 2011-09-28 |
| TW201144289A (en) | 2011-12-16 |
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